Reassessing potential economic value and health impact of effective Shigella vaccines

Abstract The gram-negative bacterium Shigella is a leading cause of diarrheal morbidity and mortality in children in low- and middle-income countries. Several promising vaccine candidates are in late stages of clinical development against this increasingly antibiotic-resistant pathogen. However, considering the increasingly crowded and costly paediatric immunization schedule, and likely advent of other important new vaccines, it is unclear whether introduction of a Shigella vaccine would represent a high priority for international agencies or health ministries in low- and middle-income countries. To determine whether there is a compelling public health value proposition for a Shigella vaccine, we used the World Health Organization’s Full Value of Vaccine Assessment analytic framework and formulated five broad scientific, policy, economic and commercial-related propositions regarding the development of a Shigella vaccine. We also explored the current regulatory, clinical, policy and commercial challenges to a Shigella-containing combination vaccine development and adoption. Through a series of literature reviews, expert consultations, social science field studies and model-based analyses, we addressed each of these propositions. As described in a series of separate publications that are synthesized here, we concluded that the economic and public health value of a Shigella vaccine may be greater than previously recognized, particularly if it is found to also be effective against less severe forms of diarrheal disease and childhood stunting. The decision by pharmaceutical companies to develop a standalone vaccine or a multipathogen combination will be a key factor in determining its relative prioritization by various stakeholders in low- and middle-income countries.


Introduction
In humans, the gram-negative bacterium Shigella causes moderate to severe diarrheal disease, including dysentery. 1 Shigellosis is also increasingly associated with other chronic and long-term conditions, 1,2 such as growth faltering or stunting in children, 3,4 and irritable bowel syndrome 5 or reactive arthritis in adults. 6However, whether these associations represent causal relationships has not yet been rigorously assessed.
After rotavirus, Shigella is the leading cause of diarrheal disease-related mortality among children younger than five years in low-and middle-income countries. 7Since transmission is associated with unclean water and poor sanitation conditions, high-risk populations other than children include travellers and military personnel staying in unsanitary settings. 1The global estimate of annual Shigella deaths in children younger than five years decreased from 600 000 in the 1990s 8 to current estimates of 28 000-64 000. 7,9,10The observed reduction may be attributable to several factors, including enhancements in living conditions, the implementation of health interventions not related to vaccines, and the advancement of disease monitoring through the use of molecular diagnostic techniques.However, treatment is becoming more complex, costly and time intensive because of Shigella's increasing resistance to antibiotics. 11Improved diagnostics have shown that antibiotic-resistant Shigella is causing more cases of acute watery diarrhoea (both severe and mild types) than previously recognized.This revelation has led researchers to revise previ-ous estimates of its etiological importance in both moderate to severe diarrhoea cases, and the more common but less severe diarrhoea. 4,12 few promising Shigella vaccine candidates are currently in Phase II or starting Phase III clinical trials with projected availability within the next 5 years. 1,13The question, however, is whether these vaccines would be sufficiently prioritized within broad policy recommendations to influence their adoption into immunization programmes in countries where Shigella is endemic. 14This uncertainty underscores the need for a broader methodological approach to evaluate the potential benefits of a Shigella vaccine.To do this, we adopted the World Health Organization's (WHO) Full Value of Vaccine Assessment framework 15 to assess the value of a Shigella vaccine for a broad range of health, societal and economic benefits at both the individual and population levels.

Assessing the value
The vaccine assessment framework 5,15 highlights the importance of a general understanding of how different aspects of introducing a new vaccine may influence the view of immunization advisory committees, health ministries and health-care providers.To gain further understanding, we formulated five scientific, policy, economic and commercial-related questions: (i) What is the evidence for the association between shigellosis, diarrhoeal disease and stunting?(ii) To what extent could a vaccine avert morbidity and mortality, health costs and larger economic consequences due to acute and long-term effects of Shigella?(iii) What is the perceived value of a Shigella vaccine to policy-makers and health-care workers in low-and middle-income countries, as well as travel medicine providers and military health policy-makers?(iv) What are the challenges and opportunities to developing and introducing a Shigellacontaining combination vaccine? and (v) What could be anticipated demand for a standalone Shigella vaccine by lowand middle-income countries as well as travellers and military?
To answer these questions we searched the literature, consulted experts, conducted social science field research, modelled health impacts and economic outcomes, and constructed demand forecasts.The results, described in a series of separate publications, are synthesized below.

Association with stunting
Several studies, including two large, multicountry analyses in low-and middle-income countries, 4,12,[16][17][18][19][20] have consistently observed statistically significant associations between moderate to severe diarrhoea, less severe diarrhoea and diminished childhood growth such as stunting.Furthermore, studies have specifically linked Shigella-attributable moderate and severe diarrhoea in in-fants and toddlers with linear growth faltering as early as 2-3 months after the initial episode; in one study, linear growth faltering was documented to persist for at least 3 years post-infection. 16,21Furthermore, children aged 12-24 months with confirmed shigellosis who were subsequently treated with antibiotics exhibited a fourfold decrease in linear growth faltering when compared to their untreated counterparts. 18lthough the incidence of Shigella-attributable diarrhoea in children aged 18-59 months is higher than in infants younger than 12 months, 16 an etiology-agnostic analysis suggests that the stunting-related consequences of moderate to severe diarrhoea appear greater at younger ages. 22Taken together, these data favour delivery of the first dose of a two-dose series by 6 months of age. 17 plausible estimate of the effect of a single Shigella-attributable diarrhoea episode would be a 0.03 length-for-age z-score decrement for children younger than 2 years, with a cumulative upper bound for all Shigella episodes of a 0.15 length-for-age z-score decrement. 17In contrast, the association of asymptomatic shigellosis with stunting is less well established.Given the current lack of evidence that Shigella vaccines could fully pre-vent infections (i.e.induce sterilizing immunity), we considered it too early to include asymptomatic shigellosis in vaccine modelling efforts. 17ypotheses regarding the underlying mechanisms by which Shigella and other entero-invasive pathogens may lead to stunting involve intestinal tract disruption, including the inflammation and intestinal tract atrophy that are hallmarks of environmental enteric dysfunction. 17Uncertainties remain whether a vaccine that is effective against shigellosis but not infection itself would affect these underlying mechanisms.Nonetheless, parenterally administered conjugate vaccines targeting other pathogens such as pneumococcus have demonstrated a substantial impact on bacterial mucosal colonization. 23here is some evidence to support that Shigella vaccines could act to alter the density or anatomical location of intestinal colonization and potentially reduce chronic inflammation. 24Vaccine probe studies are needed to directly determine the magnitude, if any, of the influence of Shigella vaccines on linear growth faltering or stunting.

Reduction in adverse outcomes
Two recent analyses 25,26 addressed the extent to which a vaccine could mitigate morbidity and mortality, reduce health-care expenses, and alleviate broader economic repercussions resulting from both the acute and long-term effects of Shigella.In the first analysis, 25, we developed a simulation model to evaluate Shigella-attributable less severe diarrhoea-associated episodes and childhood stunting in 102 low-and middle-income countries.The vaccine's hypothetical characteristics and delivery schedule were based on WHO preferred product characteristics for vaccines against Shigella. 27ccording to our simulation (without vaccination) over a 20-year period (2025-2044), Shigella is estimated to be responsible for 109 million stunting episodes, 1.4 million deaths and incur health-care expenses exceeding 11 billion United States dollars (US$).This finding suggests that an effective Shigella vaccine could potentially avert 43 million stunting cases, nearly 600 000 deaths and US$ 4.4 billion in health-care costs if available over the same 20 year period. 25    The average cost per DALY averted is US$ 849, with the vaccine being more cost-effective in the African Region (US$ 161 per DALY averted), low-income countries (US$ 143 per DALY averted) and countries eligible for support from Gavi, the vaccine alliance (US$ 308 per DALY averted).One main contributor to the lower incremental cost-effectiveness ratios 25 relative to prior analyses 28 was the inclusion of less severe diarrhoea and less severe diarrhoea-attributable stunting; a second was the assumption that in Gavi-eligible countries, a two-dose vaccine (at US$ 2 per dose) might become available rather than the previously assumed three-dose vaccine at US$ 3.30 per dose. 28We based our price estimates on the current prices of monovalent typhoid conjugate vaccines.
While the simulation suggests that Shigella vaccination may approach the cost-effectiveness of other routinely administered childhood vaccines, 25 it still probably underestimates the true economic value of the vaccine.This underestimation is because childhood linear growth faltering and stunting can ultimately influence adult height, which has been shown to be associated with differentials in labour-market wages across various low-and high-income settings. 26,29The extent to which this latter association (termed the height premium) is causal remains unclear and complex, but has been previously cited as a means to quantify future economic productivity benefits of various nutritional interventions. 29econd, we developed a benefit-cost analysis model 26 to estimate the potential productivity benefits of a vaccine that could reduce Shigella-attributable linear growth faltering relative to the net costs of a vaccine programme.This analysis 26 used the same cost, vaccine efficacy and epidemiological assumptions as the simulation model, 25 and relied on estimates of Shigella impact on growth faltering.We then applied a literature-based coefficient that translates each country-specific change in childhood length-for-age z-score to a change in adult height.Given variability in reported height premium values, we first conducted a meta-analysis of the economic literature to allow us to populate our model with a reasonable estimate. 29sing a discount rate of 3%, we determined that the benefit-cost ratio was 8.5 across all 102 low-and middle-income countries, indicating that the monetary value of benefits is higher than the costs associated with Shigella vaccination (Table 1).Benefitcost ratios were above one (parity) in all WHO regions; and highest in South-East Asia Region (15.3),Region of the Americas (10.9),African Region (8.1) and Gavi-eligible countries (14.5).We found these benefit-cost ratios to be highly robust to various sensitivity analyses.Even at only 10% effective-ness in preventing stunting, a Shigella vaccine was still predicted to provide more monetary value than its cost in most WHO regions. 26e note that neither model (simulation or benefit-cost analysis) estimated the impact of an effective Shigella vaccine on antimicrobial use and disease attributed to antibiotic-resistant Shigella strains; however modelling efforts regarding these aforementioned impacts are currently underway at WHO. [30][31]

Perceived value of a vaccine
We conducted a mixed-methods study using semi-structured individual interviews with 89 national policy-makers  and health-care providers in Burkina Faso, Ghana, Kenya, Nepal and Viet Nam, as well as with regional immunization and enteric disease experts at the Regional Office for the Americas in 2021-2022, to assess the perspectives of stakeholders in low-and middleincome countries on the introduction of a Shigella vaccine. 32We chose these five countries to represent known heterogeneity in local shigellosis burden, previous experience with diarrheal disease vaccines, stunting prevalence, and Gavi financing eligibility. 32We queried their perceptions of the relative importance of diarrheal disease, stunting, antimicrobial resistance and Shigella itself.We then explored a Shigella vaccine's potential attractiveness using the vaccine attributes and delivery schedule from WHO preferred product characteristics for vaccines against Shigella. 27he low-and middle-income countries mixed-methods study 32 revealed that diarrhoeal disease awareness was high among study participants.However, most respondents did not rank Shigella as a serious health concern for children younger than 5 years and, in the absence of additional information, more than half considered a Shigella vaccine to be a medium or low priority, with national stakeholders generally assigning a lower priority than health-care providers.Some of the reasons participants cited were lower Shigella-attributable mortality burden compared to other vaccine-preventable diseases, and large number of immunizations children currently receive.
However, when asked to consider a Shigella vaccine's potential ability to reduce antimicrobial resistance or stunting burden, more than two thirds of each group deemed the vaccine's introduction to be of medium or high priority (Fig. 3).Their strong concerns about stunting per se were especially evident in their responses to our open-ended survey questions. 32Here stakeholders called for more research into countryspecific burden and robust evidence of the long-term health impacts of a Shigella vaccine. 32n terms of vaccine delivery, study participants from low-and middleincome countries strongly preferred oral or combination Shigella vaccines over injectable or single-antigen presentations, citing greater perceived community acceptability and uptake (Fig. 4).Health-care providers generally preferred creating a new vaccination visit to administer a Shigella vaccine rather than using an existing visit, while national stakeholders' preferences were evenly divided. 32o better understand the travel medicine recommendation pathway and provider perspectives on Shigella vaccines, we interviewed 10 individuals involved in government, WHO vaccination policies and the International Society of Travel Medicine, a recognized clinical practice group of the American Society of Tropical Medicine and Hygiene.We then designed and administered an anonymous web-based survey to 31 travel medicine clinicians. 33Military perspectives were gathered from interviews, and written questionnaires administered to 11 experts in vaccine development, deployment-associated vaccine use and military public health practice from Belgium, France, Germany, United Kingdom of Great Britain and Northern Ireland and the United States of America.
Because the vaccine attributes described in WHO preferred product characteristics for vaccines against Shigella specifically refer to paediatric populations, we first confirmed that vaccine efficacy levels of 65%-80% against Shigella moderate and severe diarrhoea (if demonstrated in human challenge studies) 33 would be acceptable to travel medicine experts; for the military health policy experts, the required threshold was higher at 80%.As expected, the type of recommendations given by travel medicine providers depends largely on the degree of Shigella exposure risk in the proposed  Note: Each participant was first asked to characterize the priority of Shigella vaccine introduction, and then asked again three times following receipt of progressively more information.Participants were from Burkina Faso, Ghana, Kenya, Nepal, Viet Nam and the World Health Organization's Regional Office for the Americas.
Data source: Adapted with permission from Fleming et al. 32

Shigella combination vaccine
In 2022, 34 experts from the academic, industry, philanthropic and global health sectors with varying vaccinerelated expertise met to discuss hypothetical parenteral combinations of Shigella antigens with three existing vaccines administered to infants. 34Experts suggested that a Shigella combination vaccine conferring protection against multiple pathogens could offer myriad benefits.Some of the noted benefits include greater acceptance and better timeliness of vaccination than a standalone formulation. 35,36Other benefits could include decreases in cold chain transportation and storage space; fewer syringes; fewer needlestick accidents and other vaccine administration errors.While the cost, timing and risks associated with the development of a combination vaccine would likely be greater than for the standalone components, its potential commercial attractiveness would also be higher.
The experts concluded that the target populations of each component of a Shigella-containing combination vaccine should substantially overlap in age-incidence and geographical range.Ideally, protection against each pathogen should require the same number of vaccine doses to avoid superfluous doses.Also desirable is overlap in clinical presentation of the targeted pathogens, which brings additive or synergistic effects on disease and reductions in antimicrobial use.The experts also highlighted the need to avoid enhanced reactogenicity, and to ensure compatibility of any adjuvants or excipients included in a Shigella-containing combination vaccine. 34ne of the fundamental challenges is demonstrating the absence of clinically meaningful immunological interference between the various components of such a combination vaccine in field studies, especially when definitive immune correlates of protection are lacking for multiple antigens.The successful testing and licensure of polyvalent pneumococcal and meningococcal conjugate vaccines were also cited by the experts as an example of two potential models for registration of a Shigellacontaining combination vaccine.Like a Shigella-containing combination vaccine, demonstration of efficacy in a clinical study of each vaccine component (in this case, individual serotypes or serogroups) would be precluded by the reality that, taken separately, each was responsible for very few cases of disease.Yet precise immune correlates of protection were also lacking.While vaccine-induced antibodies that target the capsular polysaccharides of pneumococci and meningococci are believed to provide protection against disease, the specific thresholds required likely vary by serotype and serogroup, and in almost all cases remain undetermined.
To address these challenges, regulatory agencies and international agencies used innovative licensure criteria to facilitate registration of these vaccines. 34,37hese criteria include a reliance on approximate antibody thresholds as immune correlates of protection; and acceptance of the possibility that, for pneumococcal vaccines in particular, the multiple immunological comparisons required could nonetheless result in one or more components missing statistical non-inferiority, yet still allow licensure of the product as a whole.Similar approaches will likely be necessary to allow licensure, in the absence of specific immune correlates, not only of the multiserotype Shigella vaccines themselves, but also of multipathogenic Shigella-containing vaccine combinations. 34n conclusion, experts suggest that limited guidance and/or incentives available to developers of future combination vaccines will hinder their progress, and encouraged re-examination of current policy and recommendation processes to facilitate their development and availability. 34

Demand for a standalone vaccine
We created a simple market forecast model to estimate potential demand for a two-dose infant Shigella vaccine in 102 low-and middle-income countries from 2027 to 2044.For each country, we used the intervals between vaccine availability and country introduction for three recently introduced paediatric vaccines to categorize the country as an early (introduction less than five years from availability), medium (5 to 10 years) or late adopter (more than 10 years).We  used each country's coverage of three doses of diphtheria-tetanus-pertussis as a proxy for Shigella dose 1 coverage, and the first dose of measles coverage for dose 2 of the Shigella vaccine. 38The model assumed 10% wastage and a 25% buffer in the introduction year only.The model also assumed linear adoption of the vaccine over 1 to 4 years based on the size of birth cohort; with a larger birth cohort needing longer uptake time.We estimated traveller and military demand assuming a single dose scenario in the base case, and relied on summary information from publicly available sources on comparator vaccine market size, combined with prospectively-collected survey data from key stakeholders and travel medicine providers. 33We assumed pricing to be comparable to that of other traveller vaccines.

Route of administration
Our market forecast model shows that, using the most optimistic scenario where Shigella vaccine introduction follows the average historical pace of the broadly recommended rotavirus, pneumococcal conjugate and human papilloma virus vaccines, demand for Shigella vaccine in 102 low-and middle-income countries could reach nearly 200 million annual doses by 2044 (Fig. 5).We developed additional scenarios in which countries with moderate (5-20 child deaths per 100 000 persons) and low (less than five deaths per 100 000 persons) annual diarrhoeaassociated mortality rates 7 experienced 1 to 5 or 15 additional years of delay before vaccine introduction, compared to high burden countries (greater than 20 deaths per 100 000 persons).In an alternative scenario, countries would not introduce the vaccine if the incremental cost-effectiveness ratios, expressed as cost over DALYs averted, is either (i) above US$ 1000; or (ii) above the gross national income per capita. 25nder these various scenarios, demand estimates ranged from 60 million to 100 million annual doses by 2044.
Finally, we generated demand estimates for single-dose Shigella vaccines in the traveller and military markets in high-income countries in Canada and the United States as well as for the European and Western Pacific Regions. 33ssuming pre-coronavirus disease 2019 (COVID-19) pandemic travel patterns and volumes, combined annual demand among travellers and military personnel could be over 6 million doses and generate an annual revenue of US$ 576 million (range: US$ 270 million to US$ 898 million).For comparison, the global typhoid vaccine market was estimated at US$ 351 million in 2022 and projected to surpass US$ 884 million by 2030. 33

Value proposition
Shigella is responsible for a considerable proportion of less severe diarrhoea.Both less and moderate-to-severe diarrhoea have been postulated to contribute to linear growth faltering in young children living in low-and middleincome countries, with potentially profound lifetime effects on wage-earning productivity.Our analyses indicate that the potential health impact and economic value of effective Shigella vaccines are markedly enhanced compared to estimates made 5 years ago, 28 as more current models also take into account the value of preventing less-severe diarrhoea and the long-term economic effects of Shigella-associated linear growth faltering.Accordingly, including some measure of growth faltering as a robustly powered study endpoint within future efficacy studies will be critical to understand the true value of a Shigella vaccine.Similarly, as stakeholders from low-and middle-income countries highlighted the importance of Shigella antimicrobial resistance, we suggest that such studies should also assess the impact of Shigella vaccines on resistant Shigella disease and antibiotic use.
Our findings highlight the need for a comprehensive approach for Shi- gella vaccine development.We recommend that Shigella vaccine developers, funding agencies and policy-makers at both global and national level consider a broad range of potential outcomes.This approach aligns with the Full Value of Vaccine Assessment framework. 15Such a holistic review is needed, rather than basing decisions solely on our limited understanding of the immediate consequences of shigellosis.Our findings could also inform the elaboration of future guidance on Shigella vaccine preferred characteristics 27 and target product profiles by WHO 39 or others. 1 For those target product profiles, we suggest that the preferred indications for use include prevention of growth faltering in addition to the reduction of Shigella-associated antibiotic use, and antibiotic-resistant Shigella-attributed or associated disease.The preferred formulation could be a multipathogen combination vaccine; and the preferred schedule could specify that the first dose be given at 6 months of age.
Human vaccine challenge models may prove sufficient to allow licensure of the first Shigella vaccines for traveller and military populations in the coming years. 1 We believe that the substantial demand from travellers and military personnel for a standalone vaccine could further motivate vaccine manufacturers to invest in Shigella vaccines for populations in low-and middleincome countries who are most affected by shigellosis.

Resumen Reevaluación del valor económico potencial y del impacto sanitario de las vacunas eficaces contra la Shigella
La bacteria gramnegativa Shigella es una de las principales causas de morbilidad y mortalidad por diarrea en niños de países de ingresos bajos y medios.Varias vacunas candidatas y prometedoras se encuentran en las últimas fases de desarrollo clínico contra este patógeno cada vez más resistente a los antibióticos.Sin embargo, teniendo en cuenta el esquema de inmunización pediátrica, cada vez más saturado y costoso, y la probable llegada de otras vacunas nuevas importantes, no está claro si la introducción de una vacuna contra la Shigella representaría una alta prioridad para los organismos internacionales o los ministerios de salud de los países de ingresos bajos y medios.Para determinar si existe una propuesta de valor de salud pública convincente para una vacuna contra la Shigella, utilizamos el marco de análisis Full Value of Vaccine Assessment de la Organización Mundial de la Salud y formulamos cinco amplias propuestas científicas, políticas, económicas y comerciales relacionadas con el desarrollo de una vacuna contra la Shigella.clínicos, políticos y comerciales para el desarrollo y la adopción de una vacuna combinada que contenga Shigella.Mediante una serie de revisiones bibliográficas, consultas a expertos, estudios de campo de ciencias sociales y análisis basados en modelos, abordamos cada una de estas proposiciones.Como se describe en una serie de publicaciones separadas que se sintetizan aquí, llegamos a la conclusión de que el valor económico y de salud pública de una vacuna contra la Shigella puede ser mayor de lo que se reconocía anteriormente, en particular si se descubre que también es eficaz contra formas menos graves de enfermedad diarreica y retraso del crecimiento infantil.La decisión de las empresas farmacéuticas de desarrollar una vacuna independiente o una combinación multipatógena será un factor clave a la hora de determinar su prioridad relativa por parte de las diversas partes interesadas en los países de ingresos bajos y medios.

Fig. 1
illustrates the regional variability in the numbers of stunting episodes averted by vaccination and

Fig. 1 .
Fig. 1.Projected impact on Shigella-attributable stunting episodes due to the introduction of an effective Shigella vaccine, by WHO region

Fig. 2
Fig.2shows how projected decreases in stunting and other health effects would translate into averted disability adjusted life years (DALYs).The average cost per DALY averted is US$ 849, with the vaccine being more cost-effective in the African Region (US$ 161 per DALY averted), low-income countries (US$ 143 per DALY averted) and countries eligible for support from Gavi, the vaccine alliance (US$ 308 per DALY averted).One main contributor to the lower incremental cost-effectiveness ratios25 relative to prior analyses28 was the inclusion of less severe diarrhoea and less severe diarrhoea-attributable stunting; a second was the assumption that in Gavi-eligible countries, a two-dose vaccine (at US$ 2 per dose) might become available rather than the previously assumed three-dose vaccine at US$ 3.30 per dose.28We based our price estimates on the current prices of monovalent typhoid conjugate vaccines.While the simulation suggests that Shigella vaccination may approach the cost-effectiveness of other routinely administered childhood vaccines,25 it still probably underestimates the true economic value of the vaccine.This underestimation is because childhood linear growth faltering and stunting can ultimately influence adult height, which has been shown to be associated with differentials in labour-market wages across various low-and high-income settings.26,29The extent to which this latter association (termed the height premium) is causal remains unclear and complex, but has been previously cited as a means to quantify future economic productivity benefits of various nutritional interventions.29 Second, we developed a benefit-cost analysis model26 to estimate the potential productivity benefits of a vaccine that could reduce Shigella-attributable linear growth faltering relative to the net costs of a vaccine programme.This analysis 26 used the same cost, vaccine efficacy and epidemiological assumptions as the simulation model,25 and relied on estimates of Shigella impact on growth faltering.We then applied a literature-based coefficient that translates each country-specific change in childhood length-for-age z-score to a change in adult height.Given variability in reported height premium values, we first conducted a meta-analysis of the economic literature to allow us to

Fig. 2 .
Fig. 2. Disability adjusted life years potentially averted due to the introduction of an effective Shigella vaccine by WHO region

Fig. 3 .
Fig. 3. Stakeholders and health-care providers perceived priority of introducing a Shigella vaccine into the national immunization programme, low-and middle-income countries 2021-2022
33igella vaccines William P Hausdorff et al.travel destination.All agreed that vaccine attractiveness would increase if the vaccine were shown to prevent longterm sequelae and/or was combined with a vaccine targeting typhoid or hepatitis A.33 Bull World Health Organ 2024;102:65-74| doi: http://dx.doi.org/10.2471/BLT.23.290163Reassessing value of
Shigella vaccines William P Hausdorff et al.